A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo.
The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs). BCL6 lymphomagenic activity is dependent on its ability to recruit corepressor proteins to a unique binding site on its N-terminal BTB domain. A recombinant peptide fragment of the SMRT (silencing mediator for retinoid and thyroid hormone receptor) corepressor that blocks this site can inhibit BCL6 biologic functions. Shortening and conversion of this peptide to D-amino acid and retro configuration as well as the addition of a fusogenic motif yielded a far more potent and stable BCL6 inhibitor that still retained the specificity of the original SMRT fragment. Like the L-peptide, retroinverso BCL6 peptide inhibitor (RI-BPI) selectively killed BCR rather than OxPhos-type DLBCL cells. The RI-BPI could recapitulate the failure to form germinal centers seen in BCL6 null mice yet was nontoxic and nonimmunogenic even when administered for up to 52 weeks. RI-BPI showed superior duration of tissue penetration and could accordingly powerfully suppress the growth of human DLBCLs xenografts in a dose-dependent manner. Finally, RI-BPI could kill primary human DLBCL cells but had no effect on normal lymphoid tissue or other tumors.
Cerchietti
Leandro C
LC
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell College of Medicine, New York, NY 10065, USA
Yang
Shao Ning
SN
Shaknovich
Rita
R
Hatzi
Katerina
K
Polo
Jose M
JM
Chadburn
Amy
A
Dowdy
Steven F
SF
Melnick
Ari
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D066298:In Vitro Techniques; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018716:Molecular Mimicry; D056985:Nuclear Receptor Co-Repressor 2; D051560:Proto-Oncogene Proteins c-bcl-6; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D051560:Proto-Oncogene Proteins c-bcl-6; D011994:Recombinant Proteins; D012097:Repressor Proteins